This application is a 371 of PCT/GB95/02277 filed Sep. 26, 1995.
The present invention relates to the use of an alternative pharmaceutical agent in the place of Syntometrine and ergometrine for routine prevention of bleeding during or immediately after the third stage of labour. It is generally accepted that the advantages of the use of the aforementioned drugs outweigh their disadvantages and hence they are routinely administered to all women in Europe and North America immediately after delivery unless specifically contraindicated. No equally effective acceptable alternative has been introduced to the obstetric practice since these drugs were first described almost 60 years ago. I have found that Misoprostol, a drug that is widely marketed for the treatment of stomach ulcers, can fulfil the requirements of an effective agent that can be used routinely for that purpose.
The third stage of labour is potentially the most hazardous part of labour for the mother. The main risk is that of postpartum haemorrhage (PPH) with its subsequent morbidity. The rise of oxytocic drugs for the prevention of PPH has been regarded as one of the most enduring advances in medical science. The intramuscular administration of syntometrine (a combination of 5 i.u. syntocinon with 0.5 mg of Ergometrine) after the delivery of the fetus is widely practised in the developing world and has become known as the active management of the third stage of labour.
The prophylactic use of oxytocics in the third stage of labour is of particular relevance to obstetrics practice in the third world where atonic postpartum haemorrhage is a common event due to high multiparity, prolonged labour and fibroid uterus. Maternal death due to PPH is reported to be between 17 and 40% in some parts of the word (World Health Organisation 1989 and 1991). Postpartum haemorrhage is the single most common cause of maternal death in the developing world.
The concept of actively managing the third stage of labour, like many other interventions in the managements of labour, has been challenged in recent years. The first large randomised study performed in this field has shown that the routine use of syntometrine in the third stage of labour has been shown to reduce the incidence of PPH from around 18% to 5% and to reduce the length of the third stage of labour from fifteen minutes to five minutes. Further, it has been shown to reduce the need for therapeutic oxytocics from 30% to 6%. An overview of trials performed in this field strongly suggests that the routine prophylactic use of an oxytocic in the third stage of labour reduces the incidence of PPH. Despite this important problems remain.
Syntometrine is an effective combination administered by the intramuscular route, the syntocinon acting in about 2.5 minutes and the Ergometrine producing a more sustained uterotonic contraction five minutes later. However, Syntometrine is contraindicated in women with high blood pressure in pregnancy. An estimated 15% of women are therefore denied the beneficial effects of Syntometrine in the third stage of labour.
The advantages of using Syntometrine must be considered with the rare but serious side effects attributed to their hypertensive properties. Syntometrine has been known to produce a rise in blood pressure in women previously known to be normotensive. Maternal death from cardiac arrest and intracerebal haemorrhage have been attributed to Ergometrine, as have non-fatal instances of cardiac arrest and myocardial infarction. Syntometrine has also been known to be commonly associated with gastrointestinal side effects in the form of nausea and vomiting which can reduce patient acceptability.
Active management of a third stage of labour is not a universal practice. In many parts of the world, the routine use of oxytocic agents is not a practical option for various other reasons. First, oxytocic agents are not stable at high ambient temperatures and therefore require special storage requirements, for example refrigeration, over prolonged periods, Syntometrine has to be stored between 2xc2x0 and 8xc2x0 C. and protected from light. Although Syntometrine may be stored at temperatures up to 25xc2x0 C. for two months when protected from light, activity tends to decline. One study investigated the stability of Ergometrine and Methyl Ergometrine after one year of suboptimal storage which showed that 90% of the therapeutic activity of the drugs was lost over that period. The results are similar when the drug is stored in brown vials.
These requirements represent an important hurdle to the wider use of oxytocics in the developing world and accordingly, the feasibility of synthesizing forms of the drugs which are able to withstand high temperatures was considered by the World Health Organisation, (WHO) without a successful candidate being available to date.
Secondly, active management of the third stage of labour is also compromised in the third world situations because of the unknown status of the mother. Often mothers present to clinics in an advanced stage of labour when the doctor is unable to assess the likely hitherto hypertensive status of the mother and indeed is likely to be faced with difficult decisions of a more immediate nature. Because of this, oxytocics are not routinely administered, even if available in case their administration exacerbates latent hypertension.
Further, the prevalence of Hepatitis C, AIDS and other blood born diseases, in third world countries means that drugs are administered by injection only if there is no practical alternative.
Accordingly in order to find a suitable replacement for active management of the third stage of labour, a drug must have the following properties.
1. Storable at ambient temperatures with a long shelf-life.
2. Capable of stopping bleeding postpartum at low dosages and without significant side effects.
3. Having a rapid onset action.
4. Administrable by the oral or vaginal route so as to be routine for prophylaxis.
5. Have the same or an enhanced efficacy with regard to prevention of PPH and
6. Non-hypertensive or better still slightly hypotensive.
Misoprostol originally formed the subject of GB-A-1492426 which relates to synthetic 15-deoxy-16-hydroxy-16-methyl analogues of naturally occurring prostagladin E15, of the formula (1) 
wherein R1, R2 and R3 are hydrogen or an alkyl radical containing from 1 to 7 carbon atoms; R4 is an alkyl radical containing from 1 to 7 carbon atoms; R5 is hydrogen, an alkyl radical containing from 1 to 7 carbon atoms or an alkanoyl radical containing from 1 to 7 carbon atoms; R6 is an alkyl radical containing from 2 to 4 carbon atoms or a cycloalkyl radical containing from 5 to 7 carbon atoms; X is carbonyl or hydroxymethylene; V is methylene, hydroxymethylene or alkanoyloxymethylene wherein the alkanoyl radical contains from 1 to 7 carbon atoms; or, when X is carbonyl, V may also be a radical of the formula 
in which the bond represented by the dotted line in the general formula is present; Y is ethylene or vinylene; Yxe2x80x2 is vinylene, ethynylene or the group 
wherein n is 0 or 1 and R7 and R8 are hydrogen or an alkyl radical containing from 1 to 7 carbon atoms; Z is ethylene, vinylene or ethynylene; the wavy lines represent the alternative xcex1 or xcex2 sterochemical configuration or the epimeric mixture.
Our invention relates therefore to orally or vaginally administered protagladins which have significant utertonicity without adverse side effects, are rapidally absorbed orally or from a suppository via the vaginal route, are quick acting and thermostable in storage. Drugs of this type of which the prostagladin E15 analogues are preferred examples are particularly efficacious, Misoprostol itself is merely the most preferred.
Misoprostol is available under the tradename Cytotec and has been known for several years for oral administration for the healing of duodenal and gastric ulcers; including those induced by non-steroidal anti-inflammatory drugs; (NSAID).
Cytotec protects gastroduodenal mucosa by inhibiting basal, stimulated and nocturnal acid secretion; by reducing the volume of the secretion, by reducing proteolytic activity of the gastric fluid, and by increasing bicarbonate and mucosal secretion.
Cytotec is contraindicated in pregnancy because it may cause intermenstrual bleeding in pre-menopausal women. The normal oral dose is 200 xcexcg, four times a day, for use in ulcer therapy. Preclinical animal studies have shown that the drug had no effect on the uterus. However, Misoprostol has been used, without the benefit of medical intervention, in very large doses per os in Latin America as an abortifactant and lately its utertonic effects have been discussed. Prostagladins in general have been used in obstetrics for at least two decades and are widely used, often with other agents, for cervical ripening, induction of labour and induction of abortion. Some injectable prostagladins have also been used as a last resort in the treatment of critically. ill patients with intractable postpartum haemorrhage.
A prostagladin F2A has in fact already been used in one trial in 1979 to assess the efficacy of its prophylactic use in the third stage of labour. As this prostagladin can only be administered by direct injection into the uterine muscle (intramyometrially) it is inappropriate to recommend such an invasive approach for general use. Further, this group of prostagladins is associated with unacceptable side effects such that its use is only suitable in life threatening situations.
Misoprostol and its immediate analogues set out above, is an E1 prostagladin analogue which may be administered orally. Its safety is well established in the prevention and management of peptic ulcer disease.
Misoprostol has been shown in animal studies to possess a mild hypotensive effect at about 800 xcexcg in a single dose whereas at about 400 xcexcg, patients remain substantially normotensive.
As stated above, unlike oxytocic agents, I have now shown that Misoprostol and similar prostagladin analogues when administered to humans are not hypertensive up to dosages of 800 xcexcg and accordingly, by virtue of their strong utertonic features, they have an apparent superiority in the management of postpartum haemorrhage and appear to be ideal agents for prophylactic use in the third stage in labour. With regard to Misoprostol in itself; Misoprostol is already marketed as tablets for oral use, does not require special storage conditions and is known to possess a shelf-life of several years.